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The potential for the use of leghemoglobin and plant ferritin as sources of iron

  • Michał Świątek ORCID logo , Adrianna Antosik , Dominika Kochanowska , Paweł Jeżowski ORCID logo , Krzysztof Smarzyński ORCID logo , Aneta Tomczak ORCID logo and Przemysław Łukasz Kowalczewski ORCID logo EMAIL logo
Published/Copyright: December 13, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Iron is an essential component for the body, but it is also a major cause for the development of many diseases such as cancer, cardiovascular diseases, and autoimmune diseases. It has been suggested that a diet rich in meat products, especially red meat and highly processed products, constitute a nutritional model that increases the risk of developing. In this context, it is indicated that people on an elimination diet (vegetarians and vegans) may be at risk of deficiencies in iron, because this micronutrient is found mainly in foods of animal origin and has lower bioavailability in plant foods. This article reviews the knowledge on the use of leghemoglobin and plant ferritin as sources of iron and discusses their potential for use in vegetarian and vegan diets.

Keywords: plant-based diets; sources of iron; LegH; iron deficiency

1 Introduction

The type of diet is one of the main factors affecting human health. It is indicated that a diet rich in meat products, especially red meat and highly processed products, processed products, increases the risk of developing lifestyle diseases such as circulatory system diseases, heart diseases, and cancer. A diet rich in plant products is considered an example of a health-promoting diet. It is estimated that switching to plant-based diets globally could reduce the risk of premature death from non-communicable diseases by 18–21% and additionally reduce greenhouse gas emissions by 54–87% [1].

In contrast, vegetarians and vegans may be at risk of deficiencies in vitamin B12, vitamin D, iron, zinc, and calcium deficits because these micronutrients are found mainly of animal sources or have lower bioavailability in plant foods. Although plant-based diets are described as healthier for the body’s health, they should be balanced to provide the appropriate amount of nutrients needed for a healthy life every day [2,3,4,5,6].

One of the most common deficiencies occurring among human on plant-based diet is iron deficiency (ID) in serum. The reason for such a problem originated mainly in the lower bioavailability of iron from plant sources and the presence of inhibitors of iron absorption in plant-based food. Some plant-based diets are significantly restricted for the application of ingredients or technological processes, including materials from animals in food manufacturing. All those factors, as well as progress in plant-based food technologies, contribute to the development of knowledge about the possibilities of enriching the human diet with alternative iron sources in populations at risk of ID due to the exclusion of animal-based food from the diet.

The purpose of this review is to present recent knowledge about ID and its connection with plant-based diets and information about alternative iron sources such as leghemoglobin (LegH) and (plant)ferritin as a substance that are considered promising in plant-based food fortification.

2 Iron in the diet and its impact on human health

Iron is classified as a microelement that is necessary for the proper functioning of human cells. In the human body, it is a basic component involved in the transport and binding of oxygen and a cofactor of many enzymes, but it also plays an important role in the body’s immune processes. About 2/3 of the human body’s iron is found in hemoglobin, 1/4 is in the liver in the form of ferritin (FT) and hemosiderin, with the remaining sources scattered in the cytoplasm of muscle cells in the form of myoglobin [7,8].

ID is a burden contributing to the development of diseases in a significant part of the population, and the most common disease associated with ID is anemia (iron deficiency anemia, IDA). According to statistical data, the burden of IDA concerns up to 1.2 billion of the population [8]. Women (in the premenopausal period and pregnant women), but also infants and children up to 5 years of age and teenagers, are particularly susceptible to the occurrence and consequences of anemia [8]. The occurrence of ID and IDA also depends on social and demographic factors such as race/ethnicity, socioeconomic status, religion, eating habits, and diet [9,10]. Due to the high risk of IDA, preventing anemia is one of the tasks of the WHO, which aims to reduce its incidence among women by 50% [11].

ID may cause symptoms in the presence or absence of anemia or may be asymptomatic. Typical symptoms include fatigue, drowsiness, decreased concentration, dizziness, tinnitus, and pallor. In susceptible individuals, ID predisposes to restless legs syndrome [12]. Other symptoms include alopecia, dry hair or skin, and glossitis [13]. ID and anemia can also exacerbate symptoms and worsen prognosis in conditions including heart failure and coronary artery disease [14]. Preoperative anemia increases the risk of blood transfusion and is correlated with a negative course of recovery and postoperative mortality [15]. Even asymptomatic anemia has negative consequences, including impaired physical fitness, neurocognitive development of the child, and the course of pregnancy [16].

However, it is not only ID that is harmful to our health. The most frequently cited causes of iron overload (IO) are red blood cell transfusion, increased gastrointestinal iron absorption, repeated whole blood transfusions, excessive iron supplementation, chronic hepatitis, or hereditary hemochromatosis [17]. The toxicity of excessive iron content leads to serious side effects such as cardiac dysfunction, including arrhythmia and cardiomyopathy [18], liver cirrhosis, liver cancer, hepatitis [19], delayed puberty, impotence, infertility [20], metabolic disorders [21], and development of neurodegenerative diseases, e.g. Alzheimer’s [22].

The primary source of iron is the diet. For a healthy body, without metabolic disorders, achieving an appropriately balanced diet is not difficult in developed countries; therefore, ID in such populations, apart from particularly susceptible groups (children under 5 years of age, pregnant women), is usually the result of metabolic disorders, blood loss (e.g. due to heavy menstruation), as well as the ingestion of a diet with a limited supply of nutrients (e.g. plant-based diets) [23].

Iron in the human diet occurs in two forms: heme iron in organic compounds and non-heme iron occurring in inorganic compounds such as Fe2+ and Fe3+ ions. The different forms of iron found in food differ in their bioavailability. The absorption of heme iron reaches 15–35% and is only slightly dependent on the presence of inhibitors in the consumed food [24]. Heme iron has the highest bioavailability, and its best sources are meat, fish, and seafood. In a diet including products of mixed origin (plant and animal), heme iron usually constitutes approximately 10–15% of the daily iron intake [25]. The best sources of non-heme iron are seeds, grains, nuts, and dark green parts of leafy vegetables [25]. Non-heme iron occurs in various chemical forms (Fe2+ and Fe3+), which significantly affects its absorption, typically reaching levels of 2–20%, with the ferrous ion (Fe2+) being the form with the highest absorption [26]. The forms of iron present in food are low-molecular compounds, such as citrate, phosphate, phytate, oxalate, and iron hydroxide, and high-molecular compounds, such as FT (a protein that combines thousands of iron ions in the mineral core). A specific organic compound that is a source of iron in the diet of infants is lactoferrin (iron transport protein), present in breast milk and infant formulas [27,28].

Iron absorption is strongly dependent on the level of iron in the body. In case of its deficiency, iron absorption usually increases 10-fold, and this applies to both heme and non-heme iron. Moreover, the absorption of non-heme iron is influenced by both its inhibitors (phytic acid, polyphenols, calcium, milk and egg proteins, and albumins) and enhancers such as ascorbic acid and muscle tissue proteins [29]. The absorption of iron is enhanced by MFP (meat, fish, poultry) protein factors, which are present in food of animal origin such as meat, fish, and poultry products. The role of MFP factors in improving the absorption of iron supplied with food of plant origin has been demonstrated. The use of poultry, beef, or fish in the diet improves the absorption of non-heme iron two to three times compared to the absorption from a meal containing the protein equivalent of egg white albumin [30,31,32].

3 Iron in plant-based diets

Nowadays, diets that limit or completely exclude the consumption of meat products are becoming more and more popular. They are most often used by young people, especially women. Their motivation to limit the consumption of meat products is health (reducing the risk of lifestyle diseases), ethics, and the environment. A diet takes different forms depending on the type of products that are not consumed (Table 1). The lightest form is flexitarianizm, which involves limiting meat consumption to a minimum [33].

Table 1

Types of plant–based diets; the food categories included in each type of diet have been stated in table

Fruits Vegetables/grains/legumes Dairy Eggs Meat/poultry Fish
Vegetarian P P P P A A
Lacto-ovo vegetarian P P P P A A
Lacto vegetarian P P P A A A
Ovo vegetarian P P A P A A
Vegan P P A A A A
Flexitarian P P P P P P
Pesco-vegetarian P P P P A P

P – present, A – absent.

There is a variety of diets that eliminate animal products to different extents. Vegetarians are people who do not eat meat, including poultry, fish, seafood, and products containing ingredients derived from the processing of these raw materials. Lacto-ovo vegetarians exclude the consumption of meat, but their diet includes milk, eggs, and products derived from their processing. Lacto-vegetarians also exclude the consumption of eggs, unlike vegetarians, whose diet does not include milk and dairy products. Among all these variants of the vegetarian diet, intermediate variants are described resulting from different scopes of exclusion of animal products (e.g. semi-vegetarianism/flexitarian, pollotarian, pescatarian). The vegan diet does not include any products obtained from raw materials of animal origin [34,35,36]. The use of vegetarian and vegan diets (due to the richness of phytocomponents with health-promoting effects) is believed to provide attractive health-promoting properties, such as the prevention of cancer or ischemic heart disease, a beneficial effect on the reduction of BMI, low levels of total cholesterol, LDL cholesterol, and glucose [37,38].

According to studies comparing the iron content in the diet of vegetarians, lacto-vegetarians, and non-vegetarians (both among the Seventh-day Adventists population) and the diet of people consuming meat products, the type of diet and the extent to which meat and meat products are eliminated from the diet have a minimal impact on the supply of iron in the diet of the Western population. The average three-day supply of iron in the compared diet variants was 18.0 ± 1.6, 14.2 ± 0.8, 14.4 ± 0.9, and 16.1 ± 1.1 mg Fe/day, respectively [39]. The intake has been computed by the nutrient data bank providing Fe content. In contrast, assessing iron supply solely on the basis of the total Fe content in the diet is not an accurate way to assess the potential of meals to meet nutritional needs for this element. This is due to the different forms and bioavailability of iron depending on the type of food. Therefore, although a vegetarian diet provides similar amounts of iron to a diet including animal products, there are significant differences in the availability of iron for absorption, resulting from the different forms of iron (heme and non-heme) and the amount and profile of the supplied inhibitors and absorption enhancers [40,41]. The main sources of phytic acid, which is an inhibitor of iron absorption, are whole-grain products, legumes, lentils, and nuts [42,43]. Polyphenols, also limiting iron absorption, are additionally supplied with coffee, tea, red wine, and spices [25,44]. Although these factors may suggest a lower degree of meeting iron needs among people on a diet eliminating animal products, the data on this subject are not clear, and future research should include not only intake of Fe but serum analysis also.

The parameter considered appropriate to assess the degree to which the body’s iron needs are met is the analysis of serum iron. Other indicators include hemoglobin, hematocrit, and iron-binding capacity. Regardless of the selected indicators, there are no clear results on the impact of diet on the degree to which the body’s iron needs are met. The described cross-sectional studies often compare iron/FT content in people on an elimination diet and people who include meat in their diet. Some of these comparisons do not indicate statistically significant differences [41,45,46,47]. Others report significantly lower iron stores in people on a vegetarian diet [48,49,50,51]. There are also reports of a higher incidence of ID and IDA among these people, especially in women [48,52,53].

4 New sources of iron for use in plant-based diets

One of the options for supplementing iron in people on a diet eliminating animal products is the use of supplementation. However, no direct data indicates the achievement of long-term beneficial effects from such an action. In this context, there is information suggesting that iron supplementation limits the efficiency of iron absorption from meals, requires long-term use to improve the FT content in serum (observations conducted among women with low iron resources), and may additionally leads to an increase in oxidative stress due to the presence of unabsorbed iron ions in the intestine [54,55,56]. Therefore, it is suggested that a good solution is to enrich food with easily digestible iron and thus meet the demand for this element. Among the sources of iron, food producers most often use iron salts, which, however, can cause negative effects on the organism, e.g. by causing and exacerbating stomach inflammation [54,55]. Therefore, new sources of plant iron are being sought, which will be devoid of negative implications, but with high bioavailability. LegH and FT are described as the most promising.

4.1 Leghemoglobin

LegH is an oxygen-binding phytoglobin with a molecular weight of 16 kDa, first identified in the root nodules of legumes [56]. This symbiotic hemoglobin is composed of protoporphyrin IX (a heme group) and globin (a single peptide). The amino acid sequence of globin depends on the species of legume, while the heme group remains unchanged, regardless of the plant species and bacterial strain. The complex mixture of heme proteins contains two monomeric main components (LegH-a and c) and two less well-characterized minor components (LegH-b and d). Studies using ion exchange chromatography have shown that both LegH-c and LegH-d are mixtures of at least two heme proteins. The ratio of the amounts of various components of LegH depends on the age of the nodules. In the case of young root nodules, a characteristic higher content of LegH-c compared to LegH-a was observed. LegH components can also be classified, using electrophoresis, into fast-moving components (LegH-F), such as LegH-c1 and LegH-c2, and slower-moving components (LegH-S), such as LegH-a [57,58].

This hemoprotein typically consists of seven or eight helical segments A–H, with protoheme (an iron porphyrin molecule) inserted between helices E and F. Between the heme and the E-helix, there is a space called the distal pocket, which allows oxygen to approach and coordinate in a manner reversible with heme iron [59]. Helix D is present only in the β chain of hemoglobin and myoglobin; it is not present in the distal heme pocket. This is replaced by a longer interhelical CD region connecting to the critical E helix, ensuring helix mobility. Research indicates the same structure of the animal and plant hemoglobin gene, which during evolution underwent genetic rearrangement through the loss of an intron and led to changes in the amino acid sequence in approximately 80% of positions [57].

The production of LegH is possible through symbiosis between the bacteroid and the plant (Figure 1). Its synthesis begins immediately after nodulation initiation and just before nitrogenase synthesis. Symbiosis occurs in root nodules resulting from bacterial infections, and a meristem is formed in the root cortex. It divides to give rise to two types of cells – cells filled with bacteroids and smaller interstitial cells devoid of bacteroids. As a result of this division, in mature legume nodules, a structural division into three separate zones can be observed – the outer cortex, the central zone, and the inner cortex [57,60]. Endodermis – the cellular layer separating the outer and inner cortex – acts as a physical barrier to oxygen diffusion. There are no free bacteroids in the cell cytoplasm; after infection and throughout the entire period of symbiosis, bacteroids are surrounded by a symbiosomal membrane (peri-bacteroid) [61].

Figure 1 Scheme of overgrowing the roots of legume plants by bacteria of the Rhizobium genus.
Figure 1

Scheme of overgrowing the roots of legume plants by bacteria of the Rhizobium genus.

Characteristic properties of LegH include the ability to bind oxygen, similar to human hemoglobin. It binds oxygen in the nodule and establishes sufficient oxygen levels for rhizobia to respire and create ATP. It is responsible for providing bacteria with a sufficient amount of oxygen and protecting nitrogenase – an enzyme that catalyzes the environmental conversion of nitrogen to ammonia – from denaturation. Nitrogenase is an enzyme that is particularly sensitive to oxygen and is irreversibly deactivated when exposed to atmospheric oxygen. Oxygen diffusion through the dense nodule tissue would not be sufficient to meet ATP demand in the absence of LegH. For LegH to release oxygen into the bacteroid respiratory chain, its oxygen affinity must be approximately ten times lower than the oxygen affinity of bacteroid oxidase. This allows oxygen to flow through the tissue and limits the possibility of free oxygen accumulating on the surface of the bacteroid. LegH gives the nodules, which effectively fix nitrogen, their pink color. The presence of LegH in the root nodules of legumes is therefore necessary for the proper functioning of nitrogenase (Figure 2). It takes up as much as 40% of the total share of soluble proteins in papillae [57,62,63]. In addition, LegH may also influence plant metabolism, and some studies suggest that it may influence plant defense responses against pathogens. LegH is completely absent in the intercellular spaces or above other cellular organelles. The concentration of LegH in the root nodules of legumes ranges from 1–5 × 104 M [57,64].

Figure 2 Participation of LegH in the regulation of bacterial gene expression and nitrogenase functioning (prepared based on [65], available under the CC-BY license). (a) Diagram of the root nodule structure with distinction of the zones formed during the nodule development: 1 – nodule meristem, 2 – infection zone, 3 – intermediate zone, 4 – nitrogen fixation zone, 5 – aging zone. (b) Simplified model of the regulation of some bacterial genes as a result of lowering the oxygen concentration in the infection zone. LegH genes are expressed in the infection, intermediate, and nitrogen fixation zones. LegH transfers oxygen to bacterial oxidases, and these, in turn, to the respiratory chain, enabling the production of ATP in conditions of low oxygen concentration.
Figure 2

Participation of LegH in the regulation of bacterial gene expression and nitrogenase functioning (prepared based on [65], available under the CC-BY license). (a) Diagram of the root nodule structure with distinction of the zones formed during the nodule development: 1 – nodule meristem, 2 – infection zone, 3 – intermediate zone, 4 – nitrogen fixation zone, 5 – aging zone. (b) Simplified model of the regulation of some bacterial genes as a result of lowering the oxygen concentration in the infection zone. LegH genes are expressed in the infection, intermediate, and nitrogen fixation zones. LegH transfers oxygen to bacterial oxidases, and these, in turn, to the respiratory chain, enabling the production of ATP in conditions of low oxygen concentration.

The process of isolating LegH varies depending on the host plant species. The two most commonly used legumes for the production of LegH are soybeans and lupine. The first isolation methods were described already in 1980 [66]. The possibilities of using LegH in the diet are mainly related to its ability to bind oxygen. LegH has great potential as an extremely attractive component of vegetarian and vegan diets. It can be successfully used as an ingredient imitating the sensory properties of meat (texture, taste, smell) despite its plant origin, providing essential nutrients (mainly amino acids, saturated fats, sodium, and iron). The bioavailability of LegH preparations has been studied in animal models and in vitro Caco-2 cell models with different results. However, the Caco-2 model seems to be more reliable in studying the rate of bioavailability in humans. The study of Proulx and Reddy describing the effects of food supplementation with LegH indicates that the bioavailability of hemoglobin from soy root nodules is similar to that of heme iron from animal sources. When tested in the Caco-2 model, the relative biological values exhibited for LegH 27 ± 6% and bovine hemoglobin 33 ± 10% higher bioavailability than FeSO4 (P < 0.05) and with no difference between them [67]. However, future work is needed to confirm the potential ability of soy LegH in plant-based meat alternatives to contribute to iron status in vivo in humans [68]. Introducing legumes containing LegH into the diet can contribute to sustainable development, because growing plants is ecological and has less impact on the environment compared to animal breeding [69,70].

However, the production of LegH for industrial purposes is a process based on genetically modified organisms. The genes responsible for the production of LegH are introduced into plants that do not naturally contain this protein. In July 2016, a Californian company developing substitutes for meat products – Impossible Foods – introduced its flagship product – a vegan alternative to a beef hamburger [71]. In addition to improving taste and providing aroma, soy LegH protein is an excellent source of iron, similar to myoglobin, which is a source of iron in meat [72]. Currently, heme iron in the human diet is almost exclusively iron of animal origin. For the production of meatless burgers, heme is produced by a safe recombinant method using Pichia pastoris yeast genetically modified with the soy LegH gene and using a fermentation process. The yeast releases the globin; the next step is filtration until a minimum of 80% purity of LegH is obtained. It is a routine recombinant method used to produce enzymes or even drugs [73,74].

A number of studies were carried out to assess the safety of LegH obtained using in silico, in vivo, and in vitro methods. Some of them are presented in Table 2. Studies have confirmed that LegH produced in yeast has little or no allergenic potential and does not show mutagenicity in the bacterial reverse mutation test (Ames test) or clastogenicity in the chromosome aberration test under tested in vitro conditions [75]. To exclude potential systemic toxicity, a 28-day in vivo study was also performed introducing prepared LegH into the rat diet, and no negative impact on the health of females or the estrus cycle was observed. The results of all tests performed suggest that the produced protein does not raise toxicological concerns under the tested conditions. This preparation is safe and suitable for human consumption as an ingredient of a simulated meat product, with a maximum soy protein content of 0.8% [75]. The company producing the mentioned burger asked the US Food and Drug Administration (FDA) for permission to use recombinant soy LegH as an analogue of animal hemoglobin in its products [71]. The FDA granted approval in 2021, and although challenged, the consent was upheld by a decision of the federal appellate court in San Francisco [76,77]. This product has been recognized as a safe food additive (GRAS). Research has confirmed that this vegan alternative to ground beef is a better source of protein, is lower in total fat than a similarly sized beef cutlet, and contains no cholesterol. The developed preparation is produced using Pichia pastoris bacteria, whose genome has a gene encoding a given protein incorporated into it, which is why it is classified as genetically modified food in food law. Therefore, the introduction of food with the addition of LegH is not simple in legal terms, especially in European Union countries. Many countries restrict the introduction of genetically modified foods, and European Union regulations are considered the most restrictive [78]. Therefore, the introduction of LegH into wider production seems highly doubtful, which is why research is ongoing on other sources of iron.

Table 2

Review of selected studies on the allergological and/or toxicological safety of LegH

Aim of research Methods Conclusions Refs.
This article focuses on the safety, by means of allergenic potential of Pichia-derived 83 proteins, from a new simplified manufacturing process to produce LegH Prep

  1. Shotgun proteomics

  2. Mass spectrometry (IPMS)

  3. Top-down proteomics analysis

  4. Characterization of feme cofactor

  5. Bioinformatics search

  6. In vitro pepsin digestibility study of LegH

 A weight-of-evidence approach was used to determine the allergenicity of LegH Prep. No significant matches were found except for the highly evolutionarily conserved GAPDH protein. Results showed that there is an unlikely risk of cross-reactivity between LegH Prep and GAPDH [72]
To check whether food containing recombinant soy LegH produced by Pichia sp. is allergenic or toxic

  1. Sequence databases and bioinformatics search strategies (sequence of LegH and the 17 Pichia host proteins; AllergenOnline (AOL) version 2016 (v16); BLASTP in NCBI Entrez protein database; In vitro pepsin digestibility study)

  2. Pepsin activity test

  3. Determination of system’s limit of detection (LOD)

  4. - Pepsin digestion resistance tests of LegH and three control proteins

 The results demonstrate that foods containing recombinant soy LegH produced in Pichia sp. are unlikely to present an unacceptable risk of allergenicity or toxicity to consumers [79]
Safety evaluation of soy LegH protein preparation derived from Pichia pastoris, intended for use as a flavor catalyst in plant-based meat

  1. Bacterial reverse mutation assay (Ames test)

  2. Chromosome aberration assay in human peripheral blood lymphocytes

  3. 14-day dietary palatability and range finding study in rats

  4. 28-day dietary feeding study in rats

  5. 28-day investigative study with a 14-day predosing estrous cycle determination

 LegH Prep was nonmutagenic and nonclastogenic in each test. There were no mortalities associated with the administration of LegH Prep in a 28-day dietary study in male and female Sprague Dawley rats. Collectively, the results of the studies presented raise no issues of toxicological concern with regard to LegH Prep under the conditions tested [75]
Design of P. pastoris for highly secretory production of LegH without exogenous addition of expensive precursors CRISPR/Cas9 mediated genome editing methods Increased the secretion of LegH by more than 83-fold, whose maximal LegH titer and heme binding ratio reached as high as 3.5 g/L and 93%, respectively. This represents the highest secretory production of heme-containing proteins ever reported [80]
Determining the regulation of ligand binding imparted by the proximal and distal heme pockets Spectroscopic and kinetic characterization of wild-type and mutant LegH The LegH proximal heme pocket exhibits a stronger bond with bound oxygen compared to myoglobin. While myoglobin relies on additional distal pocket stabilization to lower oxygen dissociation, LegH avoids distal oxygen stabilization to prevent an excessively low dissociation rate constant. These differences in regulatory mechanisms for oxygen binding and dissociation demonstrate how LegH and myoglobin, despite their structural similarities, employ distinct strategies to control their rate constants and oxygen affinities. These strategies are tailored to meet the specific demands of their respective biological environments, allowing them to effectively facilitate oxygen diffusion [81]

4.2 (Plant)ferritin

FT exists in most plants and animals as a molecule consisting of 24 polypeptide subunits – FT heavy chain (FTH) or light type (FT light chain [FTL]). FT, consisting of 36 subunits, is also found in cardiac and skeletal muscle cells. Depending on the origin, the size of a single subunit is approximately 20 kDa (mammals) to 25–28 kDa (plants). In bacteria, FT exists as a molecule consisting of 12 subunits. The structure of the FT molecule is a protein shell filled with an iron core [82]. Plant FT is similar to the animal variety in both function and structure [83].

FT is a protein that stores Fe3+ iron ions in the cell. The FTH subunit exhibits iron oxidase activity, oxidizing it from the Fe2+ form to Fe3+. The FTL subunit, thanks to its nucleation property, leads to the formation of an iron core. In the case of animals, FT in cells of organs involved in iron storage processes (e.g. liver, spleen) is more rich in FTL subunits [84]. FT in cells maintains iron concentration at the level necessary for proper functioning (10−3–10−5 M). A single FT molecule has the ability to accumulate up to 10−2 M of iron. Typically, the iron content in a single molecule is less than 3,000 atoms [85]. Most cellular iron is stored in FT. In addition to its iron storage function, FT is also crucial in the processes that protect the cell against excess iron. Excessive amounts of iron at the cellular level may lead to the accumulation of reactive oxygen species (ROS) and oxidative damage; FT prevents such effects by binding free iron [86]. This protein also has a function in cell detoxification by directly participating in the regulation of cellular concentrations of transition metals and other metal ions apart from iron. In this way, FT limits the formation of ROS and alleviates their impact on cellular structures and macromolecules [87]. FT also plays an important role in defense against pathogen attacks. Overexpression of FT as a result of biotic stress causes complexation of iron circulating in the host body – iron becomes unavailable for the life processes of pathogens [88–90]. There is also a correlation between the FT content and the occurrence of autoimmune diseases and inflammatory conditions. Serum FT levels in patients with rheumatoid arthritis may be within the normal range, but synovial fluid and synovial cells have been shown to have elevated FT levels [91]. FT levels decrease during therapy, and FT levels help guide physicians in using glucocorticoids [92]. It has been shown that a high serum FT level is an independent risk factor for severe COVID-19 infection. Assessment of serum FT levels during hospitalization may be helpful in identifying people at high risk of severe COVID-19 disease [93,94].

FT of plant origin is considered important for assessing the possibility of its use as a source of iron in the diet [95–99]. FT from legumes is particularly popular as a source of iron [100]. The bioavailability of a protein of this origin is comparable to FeSO4 [87,101]. It is assumed that the absorption of iron from FT takes place by a mechanism independent of the process of iron absorption from FeSO4. Studies labeled 59Fe derived from FT demonstrated the bioavailability of FT iron as a feature independent of the simultaneous administration of an up to 9-fold higher dose of the mineral form in iron sulfate [102]. The likely mechanism of uptake is AP2 peptide-dependent endocytosis [103].

However, the stability of FT is ambiguously assessed. Selected studies on FT bioavailability and safety are presented in Table 3. Many authors believe that this protein is characterized by very good stability also under digestive conditions (extreme pH values) [87,104,105]. According to other experiments, FT is sensitive to gastric pH (values 1–2), leading to structural changes in the protein. However, these changes may be reversible, and the molecule returns to its native form as the pH in the intestines increases [106]. The food matrix may have a positive effect on maintaining FT stability under digestive conditions [107].

Table 3

Review of selected studies on the bioavailability and safety of plant FT

Aim of research Methods Conclusions Refs.
Effects of dietary factors on iron uptake from FT by Caco-2 cells

  1. Cell culture

  2. In vitro digestion of Ft

  3. Treatment of Caco-2 cells with dietary factors and Fe

  4. as FT or ferrous sulfate

  5. Western blots of undigested vs. digested FT

 Fe from undigested FT is absorbed by intestinal cells, and this process appears to be minimally affected by common dietary factors. However, once FT is digested, the mineralized core releases Fe, allowing for interactions with dietary factors that can influence absorption. This suggests that while dietary factors can impact the absorption of FT-bound Fe to some extent, their effect is likely comparable to or less than the influence they exert on Fe uptake from more traditional forms of iron supplementation, such as FeSO4. It’s worth noting that FeSO4, while bioavailable, can lead to undesirable changes in the color and organoleptic properties of fortified products. In contrast, FT-bound Fe, encapsulated within a mineral core and protected by a protein shell, minimizes Fe-induced oxidative damage to food products. This finding highlights the potential of using FT for biofortification of staple foods, as it offers a bioavailable source of Fe that is less prone to compromising product quality. In summary, results suggest that FT is a promising candidate for addressing iron deficiency, offering a bioavailable and food-friendly source of this essential nutrient [101]
Assessment of soy FT absorption in nonanemic women Subjects were randomly assigned to start with either a 59Fe-labeled soybean FT meal or a 59Fe-labeled FeSO4 meal, each containing 1 mg Fe, given with 60 mL of apple juice. They consumed a bagel with cream cheese after fasting for 12 hours overnight The iron status of the 16 women in the study was generally adequate, with only one participant showing slight anemia and four exhibiting ID based on low serum FT concentrations. The mean concentrations of hemoglobin and serum FT fell within expected ranges. Interestingly, there were no significant differences observed in iron absorption between the two different forms of iron or the two methods used for assessment. Both whole-body counting and RBC incorporation methods provided consistent estimates of iron absorption for both soybean FT and FeSO4. Furthermore, a notable inverse correlation was observed between serum FT levels and iron absorption, regardless of the source of iron. These findings highlight the complex relationship between serum FT and iron absorption, which appears to be consistent across different iron sources and assessment methods [104]
59Fe incorporation into red blood cells (RBCs) was measured, and after a blood draw, they received the second randomized labeled meal. Radioactivity was measured in a whole-body counter on days 14 and 28 after the second meal. A final blood sample was taken on day 28. Whole-body iron absorption was calculated based on RBC count in 5 mL of blood, assuming a blood volume of 71.4 mL/kg body weight and an 85% incorporation rate into hemoglobin
Evaluation of soybean FT intake In vitro by using human intestinal (Caco-2) cells and in vivo by using radiolabeled FT and whole-body counting in human subjects The research highlights that iron from soybeans is readily absorbed, as supported by multiple human studies. This absorption can occur through receptor-mediated endocytosis of intact FT or via DMT1 as ferrous iron, either released from digested FT or potentially from the FT iron core. Increasing the FT content in soybeans holds promise as a sustainable strategy to enhance iron absorption, particularly in vulnerable populations with ID. This avenue of investigation could contribute significantly to addressing iron-related health challenges [108]
Evaluation of gastric digestion of pea FT and modulation of its iron bioavailability by ascorbic and phytic acids in Caco-2 cells In vitro digestion/Caco-2 cell model in the presence or absence of ascorbic acid and phytic acid The study demonstrates that pea FT formation significantly increased iron bioavailability compared to the blank digest, with ascorbic acid enhancing and phytic acid decreasing its availability. However, even with ascorbic acid, the FT content in Caco-2 cells was significantly lower with pea FT compared to FeSO4. Moreover, under gastric pH conditions, no FT bands were observed in the presence of pepsin, indicating structural instability. Gel filtration chromatography and circular dichroism spectroscopy revealed pH-dependent loss of quaternary and secondary structure in pea FT. These findings suggest that the release of iron from pea FT interacts with dietary factors, ultimately affecting its bioavailability in a manner reminiscent of non-heme iron [109]
Evaluation of iron absorption from FT

  1. Radiolabeled materials

  2. Human studies

  3. Animal studies

 The study found that a nineold excess of ferrous sulfate did not impact the absorption of iron from FT. This suggests that iron in FT is not absorbed by the same mechanism as ferrous sulfate, and the absorption of FT iron remained unaffected even when saturation kinetics were maintained. Additionally, unlabeled ferrous sulfate had no significant effect on the absorption of 59Fe in FT when administered at a ratio of 9:1 (4.5 mg FeSO4 and 0.5 mg 59Fe as FT iron) in non-gastric-resistant capsules [102]

Based on the literature data presented, it can be concluded that the use of plant FT allows to provide absorbable iron, but the bioavailability depends strongly on the diet and compounds consumed in the diet that can bind iron with FT. Moreover, it should be mentioned that the use of plant sprouts containing FT in the recipes of food products may cause unfavorable changes in the appearance of these products, which may translate into their lower acceptance among consumers. However, properly thought-out ingredients of vegan products that can be enriched with FT will enable the development of a full-value product with high bioavailability and attractiveness.

5 Limitation and future perspectives

This review discusses the properties of LegH and FT as sources of Fe, as well as their role in the body. The use of new sources of iron in plant diets seems, on the one hand, necessary, but on the other hand, it poses many new risks both from the point of view of safety and bioavailability. Many countries do not allow the marketing of food containing ingredients subject to genetic modification or obtained from new GM organisms. For this reason, it seems that FT is a much more promising source of Fe for food fortification for vegans and vegetarians. Nevertheless, it is worth clearly pointing out the need to carefully analyze such enriched food, especially in the context of long-term consumption. Long-term analyses can provide valuable data that may indicate the benefits of using novel sources of Fe.

  1. Funding information: The National Centre for Research and Development of Poland (NCBR) is acknowledged for funding provided within the program LIDER under grant agreement no. LIDER/27/0105/L-11/19/NCBR/2020 (PI: Przemysław Kowalczewski).

  2. Author contributions: Each author has made an equal contribution to the composition and development of the article. Furthermore, all authors have reviewed and approved the final version of the article for publication.

  3. Conflict of interest: Przemysław Łukasz Kowalczewski, who is the co-author of this article, is a current Editorial Board member of Open Life Sciences. This fact did not affect the peer-review process.

  4. Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Received: 2023-10-08
Revised: 2023-11-08
Accepted: 2023-11-14
Published Online: 2023-12-13

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0805
Keywords for this article
plant-based diets; sources of iron; LegH; iron deficiency
Creative Commons
BY 4.0

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  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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